The proposed project will explore the hypothesis that chronic exposure to microbially-produced DNA damaging toxins such as hydrogen sulfide lead to an increased risk of colorectal cancer. According to this hypothesis, sulfate-reducing bacteria (SRBs) in colon can therefore lead to colon cancer unless their ability to generate hydrogen sulfide is attenuated by a competing metabolism such as methanogenesis. To test this, we will combine metabolic, regulatory, and evolutionary modeling with high throughput genomic technologies to explore the relationship between SRBs, methanogens, and the gastrointestinal microbial community in colorectal cancer and normal colonoscopy patients. We propose to conduct metagenome sequencing and assembly to study the possible interactions between the microbiome and hydrogen sulfide production based on the metabolic and regulatory networks of both microbes and tumors. If successful, we will have generated models that are capable of predicting the levels of various metabolite byproducts including toxic DNA damaging agents that impact the incidence of CRC and quantified the relationship between DNA damage and multiple subtypes of cancer.